Obsessive-Compulsive Disorder (OCD) is a chronic and often disabling psychiatric condition, affecting 2-4% of children and adolescents. One of the most effective treatments for OCD is Cognitive-Behavioral Therapy (CBT), yet we do not really know how CBT works in the brain. The long-term objective of this proposal is to use neuroimaging to understand what parts of the brain are affected by CBT and which of the chemical systems of the brain are involved. Such knowledge may help clinicians identify which patients are better to treat with drugs and which with CBT. This is highly relevant to the NIH mission to extend healthy life and reduce the burdens of illness and disability. This proposal will use the noninvasive neuroimaging technique of Magnetic Resonance Spectroscopic Imaging (MRSI). MRSI measures the concentrations of several neurometabolites in multiple brain regions simultaneously. The metabolites glutamate and glutamine (measured together and abbreviated as Glx) are particularly important for neurotransmission and cell energy requirements and are suspected to be disturbed in OCD. This proposal will focus on a network of brain structures called the emotion-anxiety depression circuit. In OCD patients, dysfunction is suspected in several structures comprising this circuit. In this proposal, MRSI scans will be performed twice on each of 30 children or adolescents with OCD, once before and once after a course of 12 weekly sessions of CBT. They will be compared to a second group of 30 healthy control children and adolescents who receive no treatment scanned before and after a comparable time interval. A third group of 30 OCD children and adolescents will be scanned before and after 8 weeks while they are simply waiting for treatment on our clinical treatment waitlist. After their 8 weeks are up, they, too, will receive CBT and will be scanned a third time after the 12 weekly sessions are done. All groups will also undergo clinical and neurocognitive testing at each time point. The specific aims of this proposal are: 1) Determine if levels of the metabolite Glx in the emotion-anxiety depression circuit differ between OCD patients and controls; 2) Determine levels of Glx in the circuit change after CBT and after waitlist in the OCD patients and if they change after simple passage of time in the controls; 3) Determine if there is a relationship between changes in scores on neurocognitive testing and changes in Glx levels in the three groups before and after CBT or before and after simply waiting. If successful, this proposal will establish whether Glx levels in the emotion-anxiety depression circuit are abnormal in untreated children with OCD and whether these levels change in response to CBT. If the latter is true, that will help neuroscientists and clinicians determine where in the brain CBT has its effects. Such data may be relevant to future efforts to improve OCD treatment and individual treatment matching. PUBLIC HEALTH RELEVANCE: There are effective treatments for obsessive-compulsive disorder (OCD) but even with the best available treatment most patients enjoy only partial recovery and many patients do not respond adequately at all. Such incomplete and inadequate response contributes to greater public health costs in terms of morbidity and patient care expenses. This proposal aims for a better understanding of the brain mechanisms of cognitive-behavioral therapy (CBT) in order to develop novel therapies and improve the success of existing therapies.